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Etiology of Miscarriage in Polycystic Ovary Syndrome
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I Vol. 51, No. 1, J anuary 1989
FERTILITY AND STERILITY
Printed in U.S.A.
Copyright © 1989 The American Fertility Society
Etiology of Miscarriage in Polycystic Ovary Syndrome
To the Editor: Ory/ commenting in Editor's Corner, on an article from our unit, 2 notes that the high miscarriage rate associated with the treatment of anovulatory polycystic ovary syndrome (PCOS) with pulsatile luteinizing hormone-releasing hormone (LH-RH) remains a major concern. He suggested impaired luteal function as a possible cause. On the other hand, we suggested2 that the high incidence of early pregnancy failure (miscarriage within 4 weeks of ultrasound-diagnosed ovulation) in patients with PCOS might be correlated with hypersecretion of LH during the phase of maximum follicular growth, and have since been able to confirm the association. Of 54 patients with PCOS treated with pulsatile LH-RH, 27 conceived, but 9 of these pregnancies terminated within 4 weeks of ultrasounddetected ovulation. Basal LH concentrations were significantly lower not only in those who conceived compared with those who did not, but also in those whose pregnancy progressed (n = 18, mean = 9.6 IU /1, range, 1.3 to 29.0) compared with those who suffered early pregnancy loss (n = 9, mean = 17.9 IU/1, range, 7.0 to 29.0, P = 0.01, Mann-Whitney). 3 Exposure of the ovaries to high LH concentrations during the phase of follicular growth may be deleterious to the developing oocyte. Successful fertilization and embryo development depends on ovulation of an egg matured at the appropriate time. Completion of the first meiotic division is prevented by an oocyte maturation inhibitor, which itself is inhibited by the action of LH. 4 We hypothesize, therefore, that when concentrations of LH are high in the follicular phase, as in some women with PCOS, LH penetrates the follicle and permits premature completion of oocyte maturation, resulting in ovulation of an oocyte that is physiologically 'aged.' Such oocytes may be expected to fertilize poorly and to produce embryos that implant poorly and therefore abort. In humans, extension of the interval between ovulation and donor insemination (and therefore between the completion of meiosis and fertilization) is associated with a striking increase in the rate of miscarriage.5 196
Letters-to-the-editor
These results suggest that a potentially reversible endocrine disturbance, as found in a condition as prevalent as PCOS, may underlie many cases of early miscarriage; it is possible that simple endocrine treatment may prevent what must be the very worst outcome of fertility treatment.
Roy Homburg, M.B., B.S. Research Fellow, and HowardS. Jacobs, M.D., F.R.C.P. Professor of Reproductive Endocrinology Cobbold Laboratories University College and Middlesex School of Medicine London WIN BAA United Kingdom September 7, 1988 REFERENCES 1. Ory SJ: Pulsatile luteinizing hormone-releasing hormone
2.
3.
4. 5.
therapy in women with polycystic ovarian syndrome. Fertil Steril49:941, 1988 Eshel A, Abdulwahid NA, Armar NA, Adams JM, Jacobs HS: Pulsatile luteinizing hormone-releasing hormone therapy in women with polycystic ovary syndrome. Fertil Steril 49:956, 1988 Homburg R, Armar NA, Eshel A, Adams J , Jacobs HS: The influence of serum luteinising hormone concentrations on ovulation, conception and early pregnancy loss. Br Med J 297:1024, 1988 Tsafriri A, Pomerantz SH: Oocyte maturation inhibitor. Clin Endocrinol Metab 15:157, 1986 Guerrero RR, Rojas OI: Spontaneous abortion and aging of human ova and spermatazoa. N Engl J Med 293:573, 1975
Reply of the Author: Doctors Homburg and Jacobs' efforts in elucidating the cause of early pregnancy loss in patients who have successfully undergone ovulation induction with pulsatile luteinizing hormone-releasing hormone (LH-RH) are laudable. 1 To date, assessment of early pregnancy losses has generally involved the retrospective analysis of multiple factors to identify those that might be associated with poor outcome. Thus, their potential identification of a parameter that would predict which pregnan ~ cies are at risk and would be susceptible to clinical manipulation would represent a significant contribution to the diagnosis and prevention of first trimester abortion. Their observation that patients Fertility and Sterility
with excessive serum LH levels have a higher miscarriage rate because of aberrations in follicular growth and oocyte maturation in the late follicular phase is supported by preliminary data, but remains speculative. I look forward to reading their upcoming publication in the British Medical Journal.2 They have proposed that this aberration could be corrected and higher viable pregnancy rates could be achieved if an LH- RH analog were used to suppress LH levels during the follicular phase. Filicori et al. have tested this hypothesis inducing a hypogonadotropic state with an LH-RH analog, and subsequently treating six subjects with polycystic ovary syndrome with pulsatile LH-RH. 3 Four pregnancies were achieved in nine ovulatory cycles, but two of these conceptions were spontaneously aborted. Obviously, there are multiple causes for early pregnancy loss and their preliminary observations do not resolve the role of inappropriate LH levels in impaired reproductive performance. However, their results suggest that early spontaneous abortions will continue to be a problem.
Steven J. Ory, M.D. Associate Professor of Obstetrics and Gynecology Director, Division of Reproductive Endocrinology and Infertility Mayo Clinic/Mayo Foundation Rochester, Minnesota October 10, 1988 REFERENCES
surpnsmg that two highly cost-effective procedures were not mentioned with respect to determining progestational exposure: 1. Serum samples may be obtained during the luteal phase on as many occasions as the investigator feels is optimal; these samples are stored until the full number have been collected (progesterone is an extremely stable compound in serum). Then, equal aliquots from each of the samples can be pooled in a single tube, mixed by shaking, and sent for assay of progesterone. This is essentially the same recommendation we have made many years ago for improved assessment of plasma folliclestimulating hormone (FSH) and luteinizing hormone (LH) levels. It is highly cost-effective to do one's averaging in the test tube prior to analysis, rather than getting a large number of expensive assays, and performing arithmetic. 2. There is a commercial dipstick kit for urinary pregnanediol glucuronide (Monoclonal Antibodies) where the patient simply collects urine samples; the use of the kit is an office procedure, readily performed by any office technician with a little bit of instruction, and is possibly an even more convenient and practical method of assessing progesterone production, especially since overnight urinary samples provide much more averaged and therefore representative values than plasma samples. We have found both procedures to be cost-effective and exceedingly helpful in assessing luteal phase progesterone production, whether for diagnosis or following the results of clomiphene citrate or other ovulation-induction therapy.
1. Eshel A, Abdulwahid NA, Armar NA, Adams JM, Jacobs
HS: Pulsatile luteinizing hormone-releasing hormone therapy in women with polycystic ovary syndrome. Fertil Steril 49:956, 1988 2. Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS: The influance of serum luteinizing hormone concentrations on ovulation, conception and early pregnancy loss. Br Med J. 297:1024, 1988 3. Filicori M, Campaniello E, Michelacci L, Pareschi A, Ferrari P, Bolelli G, Flamigni C: Gonadotropin-releasing hormone (GnRH) analog suppression renders polycystic ovarian disease patients more susceptible to ovulation induction with pulsatile GnRH. J Clin Endocrinol Metab, 66:327, 1988
Joseph W. Goldzieher, M.D. Professor and Director of Endocrine/Metabolic Research, and Ronald L. Young, M.D. Assistant Professor Department of Obstetrics and Gynecology Baylor College of Medicine Houston, Texas September 7, 1988 REFERENCE
Luteal Phase Deficiency
To the Editor: Reference is made to the excellent review of McNeflly and Soules 1 on luteal phase deficiency and the importance of a valid assessment of progesterone levels during the luteal phase. It is a little Vol. 51, No.1, January 1989
1. McNeely MJ, Soules MR: The diagnosis of luteal phase de-
ficiency: a critical review. Fertil Steril 50:1, 1988
Reply of the Author: The letter fr_om Drs. Goldzieher and Young brings up some interesting questions regarding the Letters-to-the-editor
197
'
L
I Vol. 51, No. 1, J anuary 1989
FERTILITY AND STERILITY
Printed in U.S.A.
Copyright © 1989 The American Fertility Society
Etiology of Miscarriage in Polycystic Ovary Syndrome
To the Editor: Ory/ commenting in Editor's Corner, on an article from our unit, 2 notes that the high miscarriage rate associated with the treatment of anovulatory polycystic ovary syndrome (PCOS) with pulsatile luteinizing hormone-releasing hormone (LH-RH) remains a major concern. He suggested impaired luteal function as a possible cause. On the other hand, we suggested2 that the high incidence of early pregnancy failure (miscarriage within 4 weeks of ultrasound-diagnosed ovulation) in patients with PCOS might be correlated with hypersecretion of LH during the phase of maximum follicular growth, and have since been able to confirm the association. Of 54 patients with PCOS treated with pulsatile LH-RH, 27 conceived, but 9 of these pregnancies terminated within 4 weeks of ultrasounddetected ovulation. Basal LH concentrations were significantly lower not only in those who conceived compared with those who did not, but also in those whose pregnancy progressed (n = 18, mean = 9.6 IU /1, range, 1.3 to 29.0) compared with those who suffered early pregnancy loss (n = 9, mean = 17.9 IU/1, range, 7.0 to 29.0, P = 0.01, Mann-Whitney). 3 Exposure of the ovaries to high LH concentrations during the phase of follicular growth may be deleterious to the developing oocyte. Successful fertilization and embryo development depends on ovulation of an egg matured at the appropriate time. Completion of the first meiotic division is prevented by an oocyte maturation inhibitor, which itself is inhibited by the action of LH. 4 We hypothesize, therefore, that when concentrations of LH are high in the follicular phase, as in some women with PCOS, LH penetrates the follicle and permits premature completion of oocyte maturation, resulting in ovulation of an oocyte that is physiologically 'aged.' Such oocytes may be expected to fertilize poorly and to produce embryos that implant poorly and therefore abort. In humans, extension of the interval between ovulation and donor insemination (and therefore between the completion of meiosis and fertilization) is associated with a striking increase in the rate of miscarriage.5 196
Letters-to-the-editor
These results suggest that a potentially reversible endocrine disturbance, as found in a condition as prevalent as PCOS, may underlie many cases of early miscarriage; it is possible that simple endocrine treatment may prevent what must be the very worst outcome of fertility treatment.
Roy Homburg, M.B., B.S. Research Fellow, and HowardS. Jacobs, M.D., F.R.C.P. Professor of Reproductive Endocrinology Cobbold Laboratories University College and Middlesex School of Medicine London WIN BAA United Kingdom September 7, 1988 REFERENCES 1. Ory SJ: Pulsatile luteinizing hormone-releasing hormone
2.
3.
4. 5.
therapy in women with polycystic ovarian syndrome. Fertil Steril49:941, 1988 Eshel A, Abdulwahid NA, Armar NA, Adams JM, Jacobs HS: Pulsatile luteinizing hormone-releasing hormone therapy in women with polycystic ovary syndrome. Fertil Steril 49:956, 1988 Homburg R, Armar NA, Eshel A, Adams J , Jacobs HS: The influence of serum luteinising hormone concentrations on ovulation, conception and early pregnancy loss. Br Med J 297:1024, 1988 Tsafriri A, Pomerantz SH: Oocyte maturation inhibitor. Clin Endocrinol Metab 15:157, 1986 Guerrero RR, Rojas OI: Spontaneous abortion and aging of human ova and spermatazoa. N Engl J Med 293:573, 1975
Reply of the Author: Doctors Homburg and Jacobs' efforts in elucidating the cause of early pregnancy loss in patients who have successfully undergone ovulation induction with pulsatile luteinizing hormone-releasing hormone (LH-RH) are laudable. 1 To date, assessment of early pregnancy losses has generally involved the retrospective analysis of multiple factors to identify those that might be associated with poor outcome. Thus, their potential identification of a parameter that would predict which pregnan ~ cies are at risk and would be susceptible to clinical manipulation would represent a significant contribution to the diagnosis and prevention of first trimester abortion. Their observation that patients Fertility and Sterility
with excessive serum LH levels have a higher miscarriage rate because of aberrations in follicular growth and oocyte maturation in the late follicular phase is supported by preliminary data, but remains speculative. I look forward to reading their upcoming publication in the British Medical Journal.2 They have proposed that this aberration could be corrected and higher viable pregnancy rates could be achieved if an LH- RH analog were used to suppress LH levels during the follicular phase. Filicori et al. have tested this hypothesis inducing a hypogonadotropic state with an LH-RH analog, and subsequently treating six subjects with polycystic ovary syndrome with pulsatile LH-RH. 3 Four pregnancies were achieved in nine ovulatory cycles, but two of these conceptions were spontaneously aborted. Obviously, there are multiple causes for early pregnancy loss and their preliminary observations do not resolve the role of inappropriate LH levels in impaired reproductive performance. However, their results suggest that early spontaneous abortions will continue to be a problem.
Steven J. Ory, M.D. Associate Professor of Obstetrics and Gynecology Director, Division of Reproductive Endocrinology and Infertility Mayo Clinic/Mayo Foundation Rochester, Minnesota October 10, 1988 REFERENCES
surpnsmg that two highly cost-effective procedures were not mentioned with respect to determining progestational exposure: 1. Serum samples may be obtained during the luteal phase on as many occasions as the investigator feels is optimal; these samples are stored until the full number have been collected (progesterone is an extremely stable compound in serum). Then, equal aliquots from each of the samples can be pooled in a single tube, mixed by shaking, and sent for assay of progesterone. This is essentially the same recommendation we have made many years ago for improved assessment of plasma folliclestimulating hormone (FSH) and luteinizing hormone (LH) levels. It is highly cost-effective to do one's averaging in the test tube prior to analysis, rather than getting a large number of expensive assays, and performing arithmetic. 2. There is a commercial dipstick kit for urinary pregnanediol glucuronide (Monoclonal Antibodies) where the patient simply collects urine samples; the use of the kit is an office procedure, readily performed by any office technician with a little bit of instruction, and is possibly an even more convenient and practical method of assessing progesterone production, especially since overnight urinary samples provide much more averaged and therefore representative values than plasma samples. We have found both procedures to be cost-effective and exceedingly helpful in assessing luteal phase progesterone production, whether for diagnosis or following the results of clomiphene citrate or other ovulation-induction therapy.
1. Eshel A, Abdulwahid NA, Armar NA, Adams JM, Jacobs
HS: Pulsatile luteinizing hormone-releasing hormone therapy in women with polycystic ovary syndrome. Fertil Steril 49:956, 1988 2. Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS: The influance of serum luteinizing hormone concentrations on ovulation, conception and early pregnancy loss. Br Med J. 297:1024, 1988 3. Filicori M, Campaniello E, Michelacci L, Pareschi A, Ferrari P, Bolelli G, Flamigni C: Gonadotropin-releasing hormone (GnRH) analog suppression renders polycystic ovarian disease patients more susceptible to ovulation induction with pulsatile GnRH. J Clin Endocrinol Metab, 66:327, 1988
Joseph W. Goldzieher, M.D. Professor and Director of Endocrine/Metabolic Research, and Ronald L. Young, M.D. Assistant Professor Department of Obstetrics and Gynecology Baylor College of Medicine Houston, Texas September 7, 1988 REFERENCE
Luteal Phase Deficiency
To the Editor: Reference is made to the excellent review of McNeflly and Soules 1 on luteal phase deficiency and the importance of a valid assessment of progesterone levels during the luteal phase. It is a little Vol. 51, No.1, January 1989
1. McNeely MJ, Soules MR: The diagnosis of luteal phase de-
ficiency: a critical review. Fertil Steril 50:1, 1988
Reply of the Author: The letter fr_om Drs. Goldzieher and Young brings up some interesting questions regarding the Letters-to-the-editor
197